The quest for an effective and safe weight loss treatment appears to be a never-ending journey. Weight loss injections have gained significant attention in recent years as a potential tool for managing obesity and associated metabolic conditions. As obesity rates continue to climb globally, these injectable medications have gained popularity among individuals seeking a more structured medical approach to weight management.
Understanding Semaglutide
Semaglutide belongs to a class of medications known as glucagon-like peptide-1 receptor agonists, or GLP-1 RAs. It mimics the GLP-1 hormone, released in the gut in response to eating. One role of GLP-1 is to prompt the body to produce more insulin, which reduces blood sugar (glucose). For that reason, health care providers have used semaglutide for more than 15 years to treat Type 2 diabetes. But GLP-1 in higher amounts also interacts with the parts of the brain that suppress your appetite and signal you to feel full. When used in conjunction with diet and exercise, it can cause significant weight loss - and a reduced risk of cancer, diabetes and heart disease - in people who are obese or overweight.
FDA Approval and Usage
The Food and Drug Administration (FDA) has approved semaglutide for chronic weight management in the 70% of American adults who are obese or overweight. The injectable drug was initially used only as a diabetes medication. Semaglutide is the first drug since Saxenda (2014) approved to treat chronic weight management. Currently, semaglutide is only approved for weight loss under the brand name Wegovy. The typical dose for weight loss is 2.4 milligrams, administered weekly as subcutaneous (under the skin) self-injections.
As interest in semaglutide for weight loss continues to grow, health care professionals are finding ways to manage the demand. Many prescribe other brands of semaglutide, such as Ozempic and Rybelsus, off-label (using a drug that is FDA-approved for a different reason). Many people use semaglutide off-label to help manage weight. The demand has become so high, that now there is a shortage for people who need this medication to help manage their diabetes.
Semaglutide: Not a Miracle Drug
Research continues to show the effectiveness of semaglutide injections for weight loss. It also highlights the value of treating obesity as a chronic metabolic disease instead of expecting people to rely solely on willpower and lifestyle changes to manage their condition. But semaglutide is not a miracle drug. And it’s not for everyone. It is important to remember that obesity is heterogenous, chronic and complex. There is no cure for obesity. It requires lifelong treatment that’s not one size fits all.
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Effectiveness of Semaglutide for Weight Loss
There have been several anti-obesity medications that help suppress appetite and achieve weight loss. But semaglutide performs on a new level. An early study of 2,000 obese adults compared people using semaglutide plus a diet and exercise program with people who made the same lifestyle changes without semaglutide. After 68 weeks, half of the participants using semaglutide lost 15% of their body weight, and nearly a third lost 20%. Participants who incorporated only lifestyle changes lost about 2.4% of their weight. Since then, additional studies have shown similar results. But they’ve also revealed that participants tend to regain the weight lost when they stop taking semaglutide. The fundamentals of obesity management will always be changes to diet and exercise. But having anti-obesity medications is another tool in the toolbox - depending on the person’s clinical history.
Clinical Trial Results
In a randomized controlled trial, participants who used semaglutide in conjunction with lifestyle interventions lost nearly 10-15% of their baseline body weight, compared to 2.5-5% in the placebo group. The mechanisms of action involve delaying gastric emptying, reducing appetite, and improving insulin sensitivity, thereby helping individuals consume fewer calories. Nevertheless, concerns remain about the durability of these effects once medication is discontinued. Ongoing research aims to clarify optimal dosing regimens, address questions about long-term safety, and explore combination therapies that might enhance outcomes further.
A clinical trial involving patients from multiple health centers found that higher doses of semaglutide may help patients achieve greater weight loss without an increased risk of side effects. Tripling the standard dose of semaglutide, a popular drug prescribed to treat obesity, led to significantly greater weight loss and associated metabolic benefits without increased risk of serious side effects, a multicenter clinical trial led by a UT Southwestern Medical Center researcher shows. Semaglutide and other drugs in its class have been life-changing for people living with obesity around the world. New findings suggest that increasing the dose can lead to even greater benefits and may be appropriate for some patients.
In the phase 3b STEP UP Diabetes trial, researchers tracked 512 adults with obesity and Type 2 diabetes assigned to three groups: 307 who took 7.2 mg of semaglutide weekly; 103 who took 2.4 mg weekly; and 102 who took a placebo. The patients - followed by medical teams at 68 sites in eight countries across Europe, southern Africa, and North America, including UTSW - stayed on these regimens for 72 weeks. As in earlier trials evaluating a 2.4 mg weekly dose of semaglutide in people with obesity and Type 2 diabetes, results showed that participants on that dose lost significantly more body weight than those on the placebo - an average of 10.4% of their starting weight, compared with 3.9%. However, those taking the higher dose lost even more weight, 13.2% on average. The STEP UP Obesity trial enrolled people living with obesity but without Type 2 diabetes.
Meta-Analysis Findings
Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. A meta-analysis was performed in accordance to the PRISMA 2020 statement. A comprehensive systematic search of PubMed/MEDLINE, Cochrane and Google scholar was performed from inception to June 2021 to identify publications in the English or foreign language with adequate English translations on semaglutide versus placebo and other GLP-1 RAs for weight loss in obesity without T2DM. The search strategy was “semaglutide” AND “obesity.” No filter was used. Ongoing trials were also sought in the relevant search. Two reviewers (HCT and MMM) independently searched the databases to identify all potentially eligible studies and reviewed the full articles for inclusion. RCTs were included in this review. Only published studies on adults with a BMI of ≥30 kg/m2 or ≥27 kg/m2 with at least one weight-related comorbidity were included. Patients with diabetes mellitus were excluded. Studies that measured percent weight loss from baseline after treatment with semaglutide were included.
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The search yielded 1208 articles, of which 263 were duplicates. After removal of duplicates and 895 articles based on title and abstract alone, 50 full text articles were assessed for eligibility, of which 46 were excluded since the studies were either done in patients with diabetes or non-obese population, used an intervention other than semaglutide, or had an outcome that was not compatible with the goals of this review. After careful evaluation, 4 RTCs were included in the review. These trials measured the percent change in body weight after treatment with semaglutide versus placebo and reported the most common adverse effects associated with treatment. Across 4 trials, 3,613 individuals were included in the study (2,350 in the semaglutide group and 1,263 in the placebo group). All trials were double blinded, randomized, using interactive web-based response system with identically looking placebo and semaglutide. There was an 11.85% mean difference for weight reduction between the treatment groups, favoring semaglutide (mean difference -11.85, 95%CI [-12.81,-10.90], p<0.00001, I2 43%).
Side Effects of Semaglutide Injections
The side effects of semaglutide are typically mild - especially when compared to the complications associated with overweight and obesity. People taking semaglutide for weight loss may experience:
- Dizziness
- Fatigue
- Gastrointestinal issues, such as diarrhea, constipation and gassiness
- Headache
- Stomach issues, including nausea, vomiting, pain or distension (bloat)
Gastrointestinal issues are the most common complaint among people just starting semaglutide. But you may be able to reduce the side effects by beginning on a lower dose and then slowly increasing the amount you take.
Gastrointestinal Adverse Events
Another outcome of this review is the risk for gastrointestinal adverse events (typically nausea, vomiting, diarrhea, constipation). The review showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide treatment (RR 1.59, 95%CI [1.34, 1.88], p< 0.00001, I2 81%). However, between-trial heterogeneity was high I2 81%, which prompted a sensitivity analysis that decreased the heterogeneity to 68%. The major source of heterogeneity was with the dose of semaglutide. The consolidation of the 4 trials also showed that patients given semaglutide were twice as likely to discontinue treatment due to adverse events (RR 2.19, 95%CI [1.36,3.55], p=0.001, I2 32%).
Serious Adverse Events
Serious adverse events were defined by the study of Rubino, Wadden and O’Neil et al., as life threatening, results in death, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect, important medical event (may jeopardize subject or may require medical/surgical intervention to prevent outcomes listed previously but may not be immediately life-threatening or result in death or hospitalization), as preventing daily activities by Wilding et al. These were reported to be uncommon. The risk for developing serious adverse events was 1.6 times more likely for semaglutide than placebo (RR1.60, 95%CI [1.24, 2.07], p=0.0003, I2 0%). O’Neil, Wilding and Rubino et al.’s studies each mentioned that death was reported during the trial period, but was not considered to be related to semaglutide or placebo treatment. No death was reported in Wadden et al.’s study.
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Additional Side Effects
They also cause reflux. They also cause nausea. They also cause abdominal cramping. A very small percentage of patients get pancreatitis, that's one of the major side effects. Nausea, delayed gastric emptying. With Ozempic, nausea is the biggest thing for patients. It's the most common reason for stopping. Some have a lot of discomfort from reflux. I've seen some patients get gallstones from the medication, but that's a common thing with weight loss in general. I've seen a few patients who've had pancreatitis as a result of medication. I haven't seen anybody with bad pancreatitis, but that certainly will happen. Some patients will get bad or lifelong pancreatitis from having taken the medication.
Who Should (and Should Not) Take Semaglutide
The FDA recommends Wegovy for weight loss if you meet one of the following criteria:
- Have a body mass index (BMI) of 27kg/m2 or greater and at least one weight-related condition, such as high blood pressure, Type 2 diabetes or high cholesterol
- Have a BMI of 30kg/m2 or greater
Avoid semaglutide if you have:
- History of medullary thyroid cancer
- History of gallbladder disease
- History of pancreatitis
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
If you’re considering semaglutide for weight loss, your first step should be consulting your primary care physician (PCP). They know your personal and family medical history and can guide you in the best treatment for your condition. Clinicians also consider factors like age, medical history, and the patient’s ability to commit to recommended lifestyle changes when determining eligibility.
Pregnant or breastfeeding individuals should also avoid these medications, as there is insufficient evidence regarding their safety in these populations. For instance, some studies indicate that individuals with uncontrolled eating disorders or severe depression might require more specialized interventions before considering pharmacological weight loss solutions.
The Future of Weight Loss Injections
Treatment for obesity is changing. Ozempic is a drug used to treat diabetes; now, millions of people are using it to lose weight. Previously, effective medical treatments for obesity were limited, with most medications offering modest weight loss. Ozempic and similar drugs now yield an average weight loss of 15 to 20 percent, significantly higher than previous options.
The class of medications called glucagon-like peptide-1 receptor agonists (GLP-1RAs) was first authorized in the early 2000s and includes semaglutide, which gained Food and Drug Administration (FDA) approval in 2017 for patients with Type 2 diabetes.
With the rise of medications such as Wegovy and Zepbound, some might think we have found the answer. But scientists and doctors say there’s still more to come when it comes to perfecting weight loss drugs and treating obesity. Current approved weight loss injections include semaglutide (Wegovy or Ozempic when used for diabetes), tirzepatide (Zepbound or Mounjaro when used for diabetes) and liraglutide (Saxenda or Victoza when used for diabetes). Semaglutide and liraglutide work by targeting one gut hormone receptor. Tirzepatide is different, because it targets two, making it a dual agonist. The next one that may get approved by the FDA is actually considered a triple agonist. But that drug, which is being developed by Eli Lilly, is still in clinical trials and hasn’t been approved by the Federal Drug Administration, yet.
Personalized Medicine and Public Health Strategies
Personalized medicine, integrating genetic, metabolic, and lifestyle data, is a key goal. Concurrently, public health strategies remain essential in addressing environmental and behavioral factors that contribute to obesity.
Multiple Drugs or Combination Drugs
I think we're looking at a future where you may be taking multiple drugs or combination drugs, either injection or pill, that hit up on these multiple hormones. If PYY [a peptide released in the small intestine that reduces appetite], which has been shown to be one of the more powerful satiety hormones, could be figured out, then we may be looking at a scenario where we can employ a system like what's used to manage blood pressure or diabetes, with multiple drugs.
Considerations Before Starting Weight Loss Injections
When considering weight loss injections, it is essential to have a clearer understanding of whether weight loss injections are a suitable option for their unique healthcare needs. Candidates may also benefit from improvements in glycemic control, blood pressure, and lipid profiles, thus reducing the risk of complications like cardiovascular disease. Adherence to medical guidance and ongoing lifestyle interventions remain vital for achieving and maintaining results.
Many healthcare professionals agree that patient education is paramount, as misunderstandings regarding drug mechanisms or unrealistic expectations can undermine success. Scientific research indicates that these medications can lead to meaningful weight reduction and metabolic improvements when paired with lifestyle interventions. Furthermore, side effects such as gastrointestinal discomfort underscore the necessity of close medical supervision. While many experts champion the role of weight loss injections as part of a comprehensive, patient-centered strategy, they also emphasize that medication alone is seldom sufficient to produce sustained change. Ultimately, informed decision-making based on current scientific evidence, expert advice, and personal health status can help patients determine whether weight loss injections are the right choice.
Lifestyle Changes
The fundamentals of obesity management will always be changes to diet and exercise. It’s unlikely the drugs will stay on the FDA’s shortage list forever. Eventually, the supply and demand should stabilize. When the new GLP-1 drugs come off the list, compounding pharmacies are supposed to stop selling semaglutide and tirzepatide, which will send many off-label patients scrambling for affordable medication. The shortages have made it difficult for some people to get GLP-1 agonists - even those with health insurance coverage for the drugs. Shortages aside, many insurers still won’t pay for GLP-1 agonists unless the patient has been diagnosed with diabetes or cardiovascular disease. A 2003 law currently prohibits Medicare from covering drugs for weight loss alone. Meanwhile, states get to decide whether to cover the drugs under Medicaid. The net result? A lot of people struggling with obesity can’t afford the most effective treatment.
To be clear, eating a lot less does drop the numbers on the scale. But exercise is still important - for your heart, bones, brain, and more. And the nutritional quality of your food matters, not just the quantity. Talya Kurzion, MS, RD, a clinical dietitian with UCSF Health, says patients taking GLP-1s should prioritize fruits and vegetables; whole grains; lean protein; and the healthy fats found in olive oil, nuts, and seeds. Of course, it’s tough to put all that advice into practice. The time and effort component of cooking healthy meals is a big barrier.
Cost and Accessibility
Weight loss injections are increasingly accessible but expensive, although some insurance plans may offer coverage. GLP-1 receptor agonists require patient education on injection technique and needle disposal. Regular medical follow-up is crucial to adjust dosages and monitor side effects. Is cost a factor? Ozempic costs about $1,200 a month, depending on the dose. There are some of these compounding pharmacies that do a generic version of it for a lot less money. I'm not so sure how comfortable we are with that. But what I do know is that people are taking the ‘generic,’ and it's not really generic; it's compounded.
Legislative efforts to expand insurance coverage for GLP-1 medications are already underway. Even if those initiatives fail, the cost of the blockbuster weight loss medications is expected to come down in the future.